Vaginal candidiasis (VC) is a fungal infection affecting approximately 75% of women at least once during their lifetimes and results in more than 40 million cases per year in the US. VC is caused by an overgrowth of endogenous Candida species, many resistant to mainstream azole antifungal therapies such as fluconazole. Azole resistance is associated with approximately 16 million recurrent VC cases per year in the US. Currently marketed azoles are fungistatic rather than fungicidal; one reason for the less than complete efficacy of these agents. Azole therapy is also associated with drug interactions and serious side-effects. There is a significant and increasing medical need for safe and effective treatments for VC that kill all Candida species known to be causative agents for VC, and that avoid drug interactions and side effects associated with current mainstream therapies. Our hypothesis is that an appropriately designed topical formulation of the novel topical antifungal agent, P-113, will meet current unmet therapeutic needs of VC patients. P113 is a 12 amino acid fragment of the salivary cationic peptide Histatin 5. P-113 and Histatin 5 are safe in humans and effective in killing both fluconazole susceptible and resistant Candida species that cause oral candidiasis, Candida species similar to those causing VC. A synthetic D amino acid P-113 isotype (P-113D) is equipotent to P113L, and avoids enzymatic degradation that might limit the in vivo effectiveness of the natural L isotype of P-113. Antifungal activity of P-113L and P-113D will be tested in vitro against fluconazole resistant Candida species across the range of physiologically significant vaginal pHs (pH 4.5 to neutral). P-113 will also be tested against physiologically beneficial Lactobacilli. P-113 drug release assays using a vaginal fluid simulant will be used to characterize drug thermodynamics in topical formulations and optimize P-113 contact with Candida species in vivo. Physical and chemical stability of at least three unique P-113 formulations will also be determined. Successful results in these studies will warrant testing P-113 in a murine VC model and toxicology studies in a future Phase II proposal.